1-(2-or 3-(4-(10,11-dihydro-dibenz(b,f)-thiepin-10-yl)-1-piperazinyl)-alkyl)-3-alkyl-2-imidazolidinone derivatives

ABSTRACT

COMPOUNDS OF THE CLASS 1-(2- OR 3-(4-(10,11-DIHYDRODIBENZ(B,F) - THIEPIN-10-YL)-1-PIPERAZINYL)-ALKYL)-3-ALKYL2-IMIDAZLIDINONE WHICH CAN BE SUBSTITUTED IN 8-POSITION OF THE DIBENZO(B,F)THIEPINE MOIETY BY CHLORO, METHYL, TRIFLUOROMETHYL, METHOXY OR METHYLTHIO AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, HAVE A DEPRESSANT EFFECT ON THE CENTRAL NERVOUS SYSTEM; PHARMACEUTICAL COMPOSITIONS COMPRISING THESE COMPOUNDS AND METHODS OF TREATMENT, PARTICULARLY METHODS OF INDUCING A DEPRESSANT EFFECT IN WARM-BLOODED ANIMALS ARE PROVIDED; AN ILLUSTRATIVE EMBODIMENT IS 1-(2-(4-(8-CHLORO-10,11-HIHYDRODIBENZO(B,F)THIEPIN-10-YL) - 1 - PIPERAZINYL)-ETHYL)-3METHYL-2-IMIDAZOLIDINONE.

"United States Patent 3,699,107 1-[2- 0R 3-[4-(10,1l DIHYDRO-DIBENZ[b,f]-

THIEPIN -YL)-1-PIPERAZINYL]-ALKYL]- T3$L YL 2 IMIDAZOLIDINONE DERIVA- E Walter Schindler, Riehen, near Basel, Erich Schmid, Basel, and Armin Ziist, Basel-Land, Switzerland, assignors to Geigy Chemical Corporation, Ardsley, N.Y. No Drawing. Filed Feb. 17, 1969, Ser. No. 799,954 Claims priority, application Switzerland, Feb. 21, 1968, 2,529/68; June 27, 1968, 9,626/68; Nov. 19, 1968,

Int. Cl. C07d 51/70 US. Cl. 260-268 TR 6 Claims ABSTRACT OF THE DISCLOSURE Compounds of the class 1-[2- or 3-[4-(10,11-dihydrodibenz[b,f] thiepin-lO-yl)-1-piperazinyl]-alkyl]-3-alkyl- Z-imidazolidinone which can be substituted in 8-position of the dibenzo [b,f]thiepine moiety by chloro, methyl, trifiuoromethyl, methoxy or methylthio and the pharmaceutically acceptable acid addition salts thereof, have a depressant effect on the central nervous system; pharmaceutical compositions comprising these compounds and methods of treatment, particularly methods of inducing a depressant efiect in warm-blooded animals are provided; an illustrative embodiment is 1- [2-[4-( 8-chloro-10,l1-dihydrodibenzo[b,f]thiepin-10-yl) 1 piperazinyl]'-ethyl]-3- methyl-Z-imidazolidinone.

This invention relates to imidazolidinone derivatives, processes for their production, pharmaceutical compositions containing these compounds and the use thereof.

More particularly, the invention relates to compounds of the formula wherein X is hydrogen, chloro, methyl, trifluoromethyl, methoxy or methylthio;

R is lower alkyl of at most 4 carbon atoms; and

n is 2 or 3; and to pharmaceutically acceptable acid addition salts thereof.

In the compounds of the general Formula I, R can be, as lower alkyl group, e.g. the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl group.

The compounds of this invention have a strong general depressant effect on oral, rectal or parenteral administration, e.g. they reduce motility, potentiate the action of anesthetics and exhibit a positive effect in the test de la traction. Furthermore, they have a pronounced sympathicolytic and antiemetic action and antagonise the action of serotonin. These properties, in combination with a favorable low toxicity, render the compounds of the invention suitable for the treatment of conditions of tension and agitation.

A preferred subclass are compounds of Formula I, wherein X is chloro, methoxy or methylthio;

R is methyl, and n is 2 or 3, and the pharmaceutically acceptable acid addition salts thereof.

3,699,107 Patented Oct. 17, 1972 "ice Preferred members of this subclass are, for example:

as well as the pharmaceutically acceptable acid addition salts thereof.

The above-mentioned pharmacological properties of the compounds of the invention are determined in experimental animals by various standard test methods [cp. R. Domenjoz and W. Theobald, Arch. int. Pharmacodyn, 120, 450 (1959); W. Theobald et al., Arch. int. Pharmacodyn, 148, 560 (1964); W. Theobald et al., Arzeimittelforschung, 17, 561 (1967)].

Thus, it is illustratively demonstrated that 1-[2-[4-(8- chloro 10,11 dihydro-dibenzo[b,f]thiepin-10-yl) 1- piperazinyl] ethyl]-3-methyl-Z-imidazolidinone dihydrochloride hydrate on intraperitoneal administration to mice in amounts of about 0.20 mg./kg., decreases the spontaneous orientation motility to a very considerable extent.

The same compound, administered in amounts of about 0.34 mg./kg. subcutaneously to mice, prevents about 50% of the animals, hanging on to a wire with their front paws, from pulling up and gripping'the wire with their hind paws (test de la traction).

The same compound, administered in amounts of about 0.5 to 20 mg./kg. subcutaneously to mice anesthetised intraperitoneally with 40 mg./kg. of the short-acting anesthetic N,N-diethyl-2-methoxy-4-allyl phenoxyacetic acid amide, potentiates, i.e. prolongs the effect of the anaesthetic to a very significant extent. The antiemetic activity of this compound of the invention as determined in goldhamsters and dogs is very pronounced. The cataleptic activity is determined in rats and is found to be only moderate.

The toxicity of the compounds of the invention as demonstrated in mice on intravenous administration is of favorable low order.

A compound of the general Formula I is produced according to the invention by reacting a compound of the general Formula II CHI-CH2 X I, and, optionally, converting the reaction product with an inorganic or organic acid into an addition salt.

Suitable reactive esters of compounds of the general Formula III are, for example, halides, such as chlorides or bromides, also sulphonic acid esters, e.g. the methane sulphonic acid ester or the or p-toluene sulphonic acid ester.

These esters are reacted with the free bases II, preferably in the presence of a solvent. Suitable solvents are those which are inert under the reaction conditions, e.g. hydrocarbons such as benzene or toluene, halogen hydrocarbons, such as chloroform, etheral liquids such as ether and dioxane as well as lower alkanones, such as acetone, methyl-ethyl lretone or diethyl ketone.

With the reaction, according to the invention, of a molecular equivalent of a reactive ester-with a molecular equivalent of a free base, a molecular equivalent of an acid is split off. This acid can be bound to the excess base of the general Formula II, or to the dibasic reaction product. Preferably, however, an acid binding agent is added to the reaction mixture. Suitable acid binding agents are, e.g. alkali metal carbonates, such as sodium and potassium carbonate, also tertiary organic bases, such as pyridine, triethylamine or especially N,N-diisopropylethylamine. Excess tertiary bases can also be used as solvents.

If, instead of the free base of the general Formula II, an alkali metal derivative of a suchlike base be used for the reactionaccording to the invention, e.g. a sodium, potassium or lithium derivative, then it is advantageous to perform the reaction in a hydrocarbon, e.g. in benzene or toluene.

Starting materials of the general Formula II, are, for example, obtained as follows:

Initial compounds are 1-0-chloro-10,11-dihydro-dibenzo[b,f]thiepins, which are substituted in the 8-position by the radical X.-- Such compounds are reactive esters of hydroxy compounds of the general Formula IV of the second processv (as defined below). They are condensed with the l-piperazine carboxylic acid ethyl ester in benzene to give the corresponding 4-(10,1l-dihydrodibenzo[b,f]thiepin-l0-yl)-l-piperazine carboxylic acid ethyl esters, which are hydrolyzed with potassium hydroxide in ethanol and simultaneously decarboxylated. Of the starting materials of the general Formula II, the 1-piperazinyl)-10,1 1-dihydro-dibenzo[b,f] thiepin is described in the literature.

The second reaction component of the process according to the invention are the reactive esters of compounds of the general Formula III. Of these compounds, the 1- (2-chloro-ethyl)-and 1-(3-chloro-propyl) 3-methyl-2- imidazolidinone and as well as the 1-(2-chloro-ethyl)- 3-butyl-2-imidazolidinone are for example known. Further compounds of this type can be obtained analogously.

Applying a second process according to the invention, a reactive ester of a compound of the general Formula IV s (IV) wherein X has the meaning given under Formula I, is reacted with a compound of the general Formula V converted with an inorganic or organic acid into an addition salt.

Suitable reactive esters of compounds of the general Formula IV are, e.g. halides such as chlorides or bro-. mides, also sulphonic acid esters, such as the methane sulphonic acid ester or the 0- or p-toluene sulphonic acid ester. Suitable as alkali metal derivatives of compounds of the general Formula V are, e.g. sodium, potassium or lithium derivatives.

The reaction, according to the invention, of the free bases or of their alkali metal derivatives with the re active esters, can be performed in the same solvents as in the case of the first process. If the free bases are used for the reaction, then the same acid binding agents can also be used.

Starting materials, reactive esters of compounds of the general Formula IV, e.g. the 10-chloro-10,1l-dihydrodibenzo[b,f]thiepin, the 8-chloro-, 8-methyl-, S-methylthioor the 8-methoxy-10-chloro-10,1l-dihydro-dibenzo [b,f]thiepin, are described in US. Pat. No. 3,351,599.

In addition, the 1-[2-(l-piperazinyl)-ethyl]-3-rnethyl- 2-imidazolidinone, the 1- [3- l-piperazinyl -propyl] -3- methyLZ-imidazolidinone, as Well as the corresponding 3-ethyl compounds, are for example known as examples of compounds of the general Formula V. Further compounds of this type can be obtained analogously.

The compounds of the general Formula I obtained using the process according to the invention, are then optionally converted in the usual manner into their addition salts with inorganic and organic acids. For example, a solution of a compound of the general Formula I in an organic solvent is mixed with the acid desired as the salt component, or with a solution thereof. Preferably, organic solvents, in which the formed salt has low solubility, are chosen for the reaction, so that the salt can be separated by filtration. Such solvents are, e.g. methanol, acetone, methyl-ethyl ketone, acetone/ ethanol, methanol/ether or ethanol/ether.

For use as medicaments, pharmaceutically acceptable acid addition salts can be used in place of free bases, i.e. salts with acids, the anions of which are not toxic in the case of the dosages in question. It is moreover of advantage if the salts to be used as medicaments crystallise well and are not, or only slightly, hygroscopic. For salt formation with compounds of the general Formula I, it is possible to use, e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, ,B-hydroxyethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, furnaric acid, maleic acid, benzoic acid, salicylic acid, phenyl acetic acid, mandelic acid and embonic acid.

As mentioned above, the new active substances are administered orally, rectally or parenterally. The dosage depends on the manner of administration, on the age of the individuum and on the particular condition to 'be treated. The daily dosages of the free bases or of pharmaceutically acceptable salts thereof, vary between 0.15 mg./kg. and 10.5 mg./kg. for warm blooded animals. Suitable dosage units, such as drages, tablets, suppositories or ampoules, preferably contain 5-200 mg. of an active substance according to the invention, or of a pharmaceutically acceptable salt thereof.

Dosage units for oral administration preferably contain as active substance between l% of a compound of the general Formula I or of a pharmaceutically acceptable salt thereof. They are produced by combining the active substance with, e.g. solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols, to form tablets or drage cores. The latter are coated, e.g. with concentrated sugar solutions,

which can also contain, e.g. gum arabic, talcum and/0rv titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of Solvents. Dyestuffs can be added to these coatings, eg. to distinguish between varying dosages of active substance.

Other suitable dosage units for oral administration are hard capsules made of gelatine as well as soft, closed capsules made of gelatine and a softener such as glycerin. The hard capsules preferably contain the active substance as a granulate, eg in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate and, optionally, stabilisers, such as sodium metabisulphite (Na S O or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, to which stabilisers can also be added.

Examples of dosage units for rectal administration are suppositories which consist of a combination of an active substance or a suitable salt thereof with a fatt foundation, or also gelatine rectal capsules which contain a combination of the active substance or a suitable salt thereof with polyethylene glycol.

Ampoules for parenteral, particularly intramuscular, administration preferably contain a water soluble salt of an active substance in a concentration of, preferably, 0.55%, in aqueous solution, optionally together with suitable stabilising agents and butter substances.

The following examples will serve to further typify the nature of the present invention, but should not be construed as a limitation on the scope thereof.

EXAMPLE 1 (a) 8.5 g. of 8-chloro-10-( 1-piperazinyl)-10,1l-dihydrodibenzo[b,f]thiepin are dissolved in 100 ml. of anhydrous acetone. 7.0 g. of potassium carbonate are added to this solution, the mixture heated to boiling and within one hour a solution of 5.0 g. of 1-(2-chloro-ethyl)-3- methyl-2-imidazolidinone in 50 ml. of anhydrous acetone is added dropwise. The reaction mixture is refluxed, while stirring, for 12 hours, then cooled and filtered. The precipitate is washed with acetone and the combined acetone solutions are completely concentrated by evaporation. The oily residue is dissolved in 2 N phosphoric acid, the solution washed with ether and made alkaline with concentrated ammonia. An oil precipitates which is taken up in benzene. The benzene solution is washed with water, dried'over sodium sulphate, intensively concentrated and mixed with a little ether. The 1-[2-[=4-(8chloro-10,1l-di hydrodibenzofib,f]thiepin yl)-1-piperazinyl]-ethyl]-3- methyI-Z-imidazolidinone crystallises out, M.P. 124-126.

The dihydrochloride is produced by dissolving 9.1 g. (0.02 mol) of the obtained base in a mixture of 10 ml. of benzene and 100 ml. of acetone and mixing the solution with ethereal hydrochloric acid until an acid reaction is obtained on congo paper. Following the addition of 100 ml. of ether, the precipitated dihydrochloride is filtered off, washed with acetone and ether and dried in vacuo. The pure 1-[2-[4-(8-chloro-10,ll-dihydrodibenzo [b,f] thiepin 10 yl) 1 piperazinyl] ethyl]-3-methyl 2 imidazolidinone dihydrochloride-monohydrate, M.P. 238-240, is obtained by recrystallising from 80% ethanol/ethyl acetate.

The starting product, the 8-chloro-10-(lpiperazinyl)- 10,11-dihydro-dibenzo[b,f]thiepin, is obtained as follows:

(b) 47.5 g. of l-piperazine carboxylic acid ethyl ester are added to a solution of 28.12 g. of 8,10-dichloro-10,11- dihydro-dibenzo[b,f]thiepin in 50 ml. of benzene. The reaction mixture is refluxed for 15 hours, cooled to and mixed with 100 ml. of 2 N ammonia. The crude free base precipitates. It is extracted three times using each time 150 ml. of methylene chloride/ether (1:2). The organic extract is washed with water, dried over magnesium sulphate and concentrated in vacuo. The residue, i.e. the 4-(8-chloro 10,11 dihydro-di benzo[b,f]thiepin-10-yl)-1- piperazine-carboxylic acid ethyl ester, is used as the crude product.

(c) The crude product obtained according to (b) is added to a solution of 61.0 g. of pulverised potassium hydroxide in 350 ml. of absolute ethanol. The obtained, cloudy solution is refluxed for 12 hours, mixed with 70 ml. of water, cooled and concentrated in vacuo. The residue is taken up in ether/methylene chloride (2:1) and water, the organic phase separated, washed with water, dried over sodium sulphate and concentrated by evaporation. The crude base is dissolved in 250 ml. of ether and 50 ml. of ethanol and the solution is neutralised with ethereal hydrochloric acid. The S-chloro-lO-(l-piperazinyl) -10, 1 1-dihydro-dibenzo[b,f]thiepin-dihydrochloride precipitates. It is filtered off, washed with a little acetone, whereupon it melts at 195200.

EXAMPLE 2 I (a) 4.5 g. of 1-[2-(l-piperazinyl)-ethyl]-3-methyl-2- imidazolidinone in 50 ml. of anhydrous acetone are added dropwise, while stirring, to a solution of 5.8 g. of 8,10- dichloro-10,l1-dihydrodibenzo[b,f]thiepin and 2.3 g. of N,N-diisopropyl-ethyl-amine in 50 ml. of absolute benzene at 10-15. The reaction mixture is refluxed, while further stirring, for 12 hours, then cooled to room temperature and mixed with water. The benzene solution is separated, thoroughly washed with water and is extracted four times with 2 N phosphoric acid solution. The clear, acid extract is made alkaline with concentrated ammonia, whereby the free base precipitates. It is separated and crystallised from benzene ether. The obtained l-[2-[4-(8-chloro-10,1l-dihydro dibenzo[b,f]thiepin 10 yl) 1 piperaziny1]- ethyl1-3-methyl-2-imidazolidinone melts at l24-l26.

The same end product may also be obtained in the following manner:

(b) A solution of 1.26 g. (0.011 mol) of methane sulphochloride in 10 ml. of absolute benzene is added dropwise at 0, while stirring well, to a solution of 2.63 g. (0.01 mol) of 8-chloro-10-hydroxy-10,1l-dihydro-dibenzo [b,f]thiepin and 0.87 g. (0.011 mol) of pyridine in 20 ml. of absolute benzene. The reaction mixture is stirred for 5 hours at 2030 and 2.33 g. (0.011 mol) of 1-[2-(lpiperazinyl)-ethyl]-3-methyl- 2-imidazolidinone are then added. After being refluxed for 15 hours, the mixture is poured on to ml. of ice water and mixed with 20 ml. of 2 N sodium hydroxide solution.

The organic layer is separated, washed with water and shaken out with 50 ml. of l-molar aqueous methane sulphonic acid solution. The acid aqueous extract is then made alkaline with 10 ml. of concentrated sodium hydroxide solution and shaken out with ether/methylene chloride (2: 1). The organic extracts are then washed with water, dried over magnesium sulphate and the solvent removed under vacuum.

The obtained crude base is taken up in acetone and the dihydrochloride is precipitated with ethereal hydrochloric acid. After filtration, the dihydrochloride is washed with acetone/ether and dried in vacuo.

The pure 1-[2-[4-(8-chloro-10,l1-dihydro-dibenzo[b.f] thiepin 10 yl) 1 piperazinyl] ethyl] 3 methyl 2- imidazolidinone-dihydrochloride monohydrate, M.P. 238- 240, is obtained after recrystallisation from 80% ethanol/ethyl acetate.

EXAMPLE 3 17.1 g. (0.062 mol) of 8-methoxy-lO-chloro-l0,11-dihydrodibenzo[b,f]thiepin are dissolved in ml. of methyl-ethyl ketone and 1.0 g. of pulverised potassium iodide, 5.0 g. (0.03 mol) of potassium carbonate, 14.4 g. (0.068 mol) of 1-[2-(l-piperazinyl)-ethyl]-3-methyl-2- imidazolidinone are added. The mixture is refluxed for 24 hours. It is then allowed to cool, the formed suspension is filtered by suction, then washed with methyl-ethyl ketone and concentrated in vacuo at 40. The residue is dissolved in ethyl acetate and water and the aqueous phase is separated. The organic phase is heated to 60 and extracted with 2- N hydrochloride acid heated to 60. The light yellow crystals of the Z-methoxy-dibenz[b,f]thiepin, which precipitate, are filtered with suction.

The acid aqueous solution is subsequently cooled to 20. It is made alkaline with concentrated ammonia and the free, precipitated base extracted with acetic acid ethyl ester. The organic extract is dried over calcium chloride and is concentrated by evaporation in vacuo, whereby a light-orange resin is obtained, which crystallises. The crude product is recrystallised from acetonitrile, whereupon the 1-[2-[4-(8-methoxy-10,11-dihydro-dibenzo[b,f] thiepin 10 yl) 1 piperazinyl] ethyl] 3 methyl 2- imidazolidinone is obtained, which melts at 125.5127.5.

The obtained base is dissolved in methyl-ethyl ketone and ethanolic hydrochloric acid is added until an acid reaction is shown on congo paper, whereupon the dihydrochloride precipitates. The obtained 1-[2-[4-(8-methoxy 10,11 dihydro dibenzo[b,f]thiepin 10 yl) 1- piperazinyl] ethyl] 3 methyl 2 imidazolidinonedihydrochloride melts at 236238.

EXAMPLE 4 10.0 g. (0.034 mol) of 8-methylthio-10-chloro-l0,11- dihydro-dibenzo[b,f] thiepin are dissolved in 75 ml. of absolute benzene and 14.4 g. (0.068 mol) of 1-[2-(1- piperazinyl)-ethyl]-3-methyl-2-imidazolidinone are added dropwise at to this solution. The reaction mixture is refluxed for 16 hours and washed with a mixture of 5 ml. of 2 N sodium hydroxide solution and 100 ml. of water. The organic phase is then extracted with 100 ml. of molar citric acid. The crude free base is precipitated with sodium hydroxide solution from the acid extract and is extracted with ether/methylene chloride (2:1). The ether/ methylene chloride solution is dried over magnesium sulphate and concentrated by evaporation. The residue is dissolved in 50 ml. of acetone, the solution diluted with 350 ml. of ether and mixed with ethereal hydrochloric acid until an acid reaction is obtained on congo paper. The precipitated dihydrochloride is washed with ether and dried in vacuo. The obtained 1-[2-[4-(8-methylthio-10,1l-dihydro dibenzo [b,f]thiepin yl) 1-piperazinyl]-ethyl]- 3-methyl-2-imidazolidinone-dihydrochloride melts at 212- 214.

EXAMPLE 5 14.0 g. (0.05 mol) of 8,l0-dichloro-10,ll-dihydro-dibenzo[b,f]thiepin and 22.6 g. (0.1 mol) of 1-[3-(1-piperazinyl)-propyl]-3-methyl-Z-imidazolidinone are dissolved in 100 ml. of absolute toluene and the mixture is refluxed for hours. The reaction mixture is then mixed with 100 ml. of water and 10 ml. of 2 N sodium hydroxide solution, well shaken and the organic phase is separated. The organic phase is washed five times with 200 ml. of water each time and is then extracted with a l-molar aqueous methane sulphonic acid solution. The acid aqueous extract is made alkaline with concentrated sodium hydroxide solution and extracted with ether/methylene chloride (2:1). The organic phase is washed with water, dried over magnesium sulphate and is concentrated to dryness in vacuo. Theresidue, the obtained crude base, is dissolved in ether and the dihydrochloride is precipitated with ethereal hydrochloric acid. The obtained 1-[3-[4-(8- chloro 10,1l-dihydro-dibenzo[b,f]thiepin-10-yl)-1piperazinyl] propyl] 3 methyl 2 imidazolidinone dihydrochloride melts at 208-210 after recrystallising from ethanol.

The following end products are obtained in an analo gous manner:

(a) From 12.0 g. (0.048 mol) of 10-chloro-10,11-dihydro-di-benzo[b,f]thiepin and 20.5 g. (0.097 mol) of 1- [2- 1-piperazinyl)-ethyl] -3-methyl-2-imidazolidinone is obtained the l-[2-[4-(10,1l-dihydro-dibenzo[b,f]thiepin- 10-yl)-1-piperazinyl]-ethyl] 3 methyI-Z-imidazolidinone, M.P. 146-148 (from benzene/petroleum ether), the dihydrochloride, M.P. 216-218 (from 90% ethanol/ether).

(b) From 13.0 g. (0.05 mol) of 8-methyl-10-chloro- 10,1l-dihydrodibenzo[b,f]thiepin and 21.2 g. (0.1 mol) of 1- [2- 1 -piperazinyl) -ethyl] -3 -methyl-2-imidazolidinone is obtained the 1-[2-[4-(.8-methyl-1-0,1l-dihydro-dibenzo- [b,f]thiepin-10-yl) 1 piperazinyl]-ethyl]-3-methyl-2- imidazolidinone, M.P. 129-131", the dihydrochloride, M.P. 208-210, and

(c) From 0.05 mol of 8-trifiuoromethyl-10-chloro-10, 1l-dihydro-dibenzo[b,f]thiepin and 0.1 mol of 1-[2-(1- piperazinyl) -ethyl]-3-methyl-2-imidazolidinone is obtained the 1-[2-[4-('8trifiuoromethyl-10,1l-dihydrodibenzo[b,f] thiepin-IO-yl)-1-piperazinyl] 3 methyl-Z-imidazolididone.

EXAMPLE 6 16.5 g. (0.05 mol) of 8-chloro-10-(l-piperazinyD-IO, 11-dihydro-dibenzo[b,f]thiepin, 10.6 g. (0.0 6 mol) of 1- (3-chloropropyl)-3-methyI-Z-imidazolidinone and 13.8 g. of potassium carbonate in 1 00 ml. of diethyl ketone are refluxed for 36 hours. The reaction mixture is poured on to 300 ml. of ice water and mixed with 50 ml. of 2 N sodium hydroxide solution.

The organic layer is separated and the aqueous phase extracted with ether/ methylene chloride (2: 1). The combined organic extracts are washed with water and then extracted with a l-molar solution of methane sulphonic acid. The acid aqueous extracts are then made alkaline with concentrated sodium hydroxide solution and extracted with ether/ methylene chloride (2:1). After washing with water, the organic extracts are dried over magnesium sulphate and the solvents removed under vacuum.

The obtained oily, crude base is dissolved in acetone and the dihydrochloride is precipitated with ethereal hydrochloric acid. After the addition of ether, the product is filtered off, washed with acetone/ether and dried in vacuo. The pure 1-[3-[4-(8-chloro- 10,11-dihydro-dibenzo- [b,f]thiepin-l0-yl) 1 piperazinyl]-propyl]-3-methyl-2- imidazolidinone-dihydrochloride, M.P. 208-21-0, is obtained by recrystallising from absolute ethanol/ether.

EXAMPLE 7 The following end product is obtained analogously to Example 6:

(a) From 6.2 g. (0.018 mol) of S-methylthio-lO-(lpiperazinyl)-10,1l-dihydro-dibenzo[b,f]thiepin and 4.3 g.

(0.0241 mol) of 1-(3-chloro-propyl)-3-methyl-2-imidazolidinone is obtained the 1-[3-[4-(8-methylthio-10,1l-dihydro-dibenzo[b,f]thiepin-IO-yl) l piperazinyl1-propyl]-3-methyl 2 imidazolidinone-dihydrochloride, M.P. 212-2l5 (from abs. ethanol/ethyl acetate).

The 8-methylthio-1 0-( 1-piperaZinyl)-l0,1 l-dihydroedibenzo[b,f]thiepin, which is used asthe starting material, is obtained as follows:

(b) 26.9 g. (0.092 mol) of 8-methylthio-10 chloro- 10,11-dihydro-dibenzo[b,f] thiepin, M.P. 106-109 are dissolved in 60 ml. of absolute benzene and 47.4 (0.3 mol) of l-piperazine carboxylic acid ethyl ester are added. The reaction mixture is refluxed for 20 hours, poured on to 500 m1. of ice water and extracted with 800 ml. of a mixture of ether/methylene chloride (2:1). The organic extract is washed six times with water, dried over magnesium sulphate and concentrated by evaporation in vacuo. The obtained 4-(8-methylthio-l0,1l-dihydro-dibenzo[b,f] thiepin-LO-yl)-l-piperazine carboxylic acid ethyl ester is used as the crude product.

(c) 42.0 g. of crude 4-(8-methylthio-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazine carboxylic acid ethyl ester are added to a solution of 64.0 g. of potassium hydroxide in 400 ml. of absolute ethanol. The reaction mixture is refluxed for 16 hours. The ethanol is then distilled off from the mixture, the residue poured on to ice water and the suspension extracted with ether/ methylene chloride (2:1). The organic extract in washed with water until the pH is adjusted to 8. The organic solution is then dried over magnesium sulphate and concentrated by evaporation in vacuo. The obtained crude product is taken up in ml. of absolute acetone, mixed with 9 ethereal hydrochloric acid and the precipitated hydrochloride is recyrstallised from 96% ethanol/ether. The obtained pure -8-methy1thio-'10'-(1-piperazinyl)-10,1l-dihydro-dibenzo[b,f]thiepin-hydrochloride melts at 220-222".

EXAMPLE 8 The following end product is obtained analogously to Example 6:

(a) From 7.9 g. (0.0244 mol) of 8-methoxy-10-(1- piperazinyl)-10,1l-dihydro-dibenzo[b,f]thiepin and 4.55 g. (0.028 mol) of 1-(2-chloro-ethyl)-3-methyl-2-imidazolidinone is obtained the 1-[2-[4-(8-methoxy-10,1l-dihyd re-dibenzo[b,f]thiepin-10-yl) 1 piperazinyl]-ethyl]-3- methyl 2 imidazolidinone-dihydrochloride, M.P. 236- 238.

The starting product, the 8-methoxy-l0-(1-piperazinyl)- 10,1l-dihydro-dibenzo[b,f]thiepin, is obtained as follows:

(b) From 8-methoxy-l0-chloro-10,1l-dihydro-dibenzo- [b,f]thiepin and l-piperazine carboxylic acid ethyl ester is obtained the 4-(8-methoxy-10,1l-dihydro-dibenzo[b,f] thiepin-10-yl)-1-piperazine carboxylic acid ethyl ester, M.P. 100-102, analogously to Example 7b.

(c) Analogously to Example 70, the 8-methoxy-10-(1- piperazinyl) 10,11 dihyd-ro-dibenzo[b,f]thiepin, M.P. 105-107, is obtained from the ester obtained according to (b).

The free base may be converted in acetone by means of ethereal hydrochloric acid into the dihydrochloride, which melts at l79181 after recrystallising from ethanol/ethyl acetate.

EXAMPLE 9 Analogously to Example 6, from 17.1 g. (0.05 mol) of S-rnethylthio l l-piperazinyl)-l0,1l-dihydro-dibenzo- [b,f]thiepin and 9.75 g. (0.06 mol) of 1-(2-chloro-ethyl)- 3-methyl-2-imidazolidinone is obtained the 1-[2-[4-(8- methylthio 10,11 dihydro-dibenzo[b,f]thiepin-l-O yl)-1- piperazinyl] ethyl]-3-methyl-2-imidazolidinone dihydrochloride, M.P. 212-214 (from 90% ethanol/ether).

EXAMPLE 10 The following end product is obtained analogously to Example 6:

(a) From 11.6 g. (0.035 mol) of 8-chloro-10-(1-piperazinyl) 10,11 dihydro-dibenzo[b,f]thiepin and 8.5 g. (0.048 mol) of 1-(2-chloro-ethyl)-3-ethyl-2-imidazolidinnone is obtained the 1-[2-[4-(8-chloro-10,1l-dihydro-dibenzo[b,f]thiepin-10-yl) 1 piperazinyl]-ethyl]-3-ethyl- Z-imidazolidinone dihydrochloride, M.P. 202-205 (from 85% ethanol/ethyl acetate).

The 1-(2-chloro-ethyl) 3 ethyl-2-imidazolidinone, which is required as starting material, is obtained as follows:

(b) 115.1 g. (1.0 mol) of N-ethyl-2-oxazolidinone with 116 g. (1.1 mol) of 2-chloro-ethyl isocyanate and 10.0 g. of lithium chloride are heated for 2 hours at 180. The reaction mixture is cooled, mixed with 300 ml. of chloroform and extracted three times with 30 ml. of a saturated aqueous sodium chloride solution. The organic layer is separated, dried over magnesium sulphate and the solvent isremoved under vacuum. The residue is distilled in high vacuum and yields the 1-(2-chloro-ethyl)-3-ethyl-2-imidazolidinone, B.P. 97-l00/0.01 torr, n =l.4913.

EXAMPLE 11 The following end product is obtained analogously to Example 6:

(a) From 13.2 g. (0.04 mol) of 8-chloro-10-(1-piperazinyl) 10,11 dihydro-dibenzo[b,f]thiepin and 9.85 g. (0.048 mol) of 1 (2-chloro-ethyl)-3-butyl-2-imidazolidinone is obtained the 1-[2-[4-(8-chloro-10,1l-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl] 3 butyI-Z-imidazolidinone-dihydrochloride, M.P. 205-208 (from ethanol/ ether).

The 1-(2-chloro-ethyl) 3 butyl 2 imidazolidinone, which is required as the starting material, is obtained as follows:

(b) 292 g. (2.5 mol) of N-butylamino-ethanol with 295 g. (2.5 mol) of diethyl carbonate and with the addition of 1 g. of sodium are slowly heated to reflux temperature. The ethanol formed during the reaction is continuously distilled off on a column. In the course of 3-4 hours, the flask temperature is increased to whereby 215 g. of ethanol-distillate are collected.

The residue is fractionally distilled in vacuo. The pure 'N-butyl-Z-oxazolidinone boils at B.P.: 150/ 12 torr, n =1.4536.

(c) 107.3 g. (0.75 mol) of the product obtained according to (b) are reacted with 87.0 g. (0.825 mol) of 2-chloroethyl isocyanate in the presence of 7.5 g. of lithium chloride, analogously to Example 10b, to give the 1-(2-chloroethyl)-3-butyl-2-imidizalidinone, B.P. 105110/0.01 torr, n 1.4859.

EXAMPLE l2 Analogously to Example 6, from 10.0 g. (0.03 mol) of 8-chloro-l0-(l-piperazinyl) 10,11 dihydro-dibenzo[b ,f] thiepin and 6.9 g. (0.036 mol) of 1-(3-chloro-propyD-3- ethyI-Z-imidazolidinone is obtained the 1-[3-[4-(8-chloro- 10,11 dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]- propyl]-3-ethyl-2-imidazolidinone-dihydrochloride, M.P. 183-186 (from ethanol/ether).

The 1-(3-chloro-propyl) 3 ethyI-Z-imidazolidinone, which is required as the starting material, is obtained, analogously to Example 10b, from 60 g. (0.52 mol) of N-ethyl-Z-oxazolidinone and 68 g. (0.57 mol) of 3-chloropropyl-isocyanate in the presence of 4.8 g. of lithium chloride, B.P. 105-110/0.01 torr, n =l.4889.

EXAMPLE 13 Analogously to Example 6, from 12.1 g. (0.037 mol) of 8-methoxy-10-(l-piperazinyl) 10,11-dihydro-dibenzo [b,f]thiepin and 8.5 g. (0.048 mol) of 1-(3-chloro-propyl)-3-methyl-2-imidazolidinone is obtained the 1-[3-[4- (S-methoxy 10,11 dihydro-dibenzo[b,f]thiepin-10-yl)- 1 piperazinyH-propyl]-3-methyl-2-imidazolidinone-dihydrochloride, M.P. 195-l97 (from ethanol/ether).

EXAMPLE 14 Analogously to Example 6, from 12.1 g. (0.037 mol) of 8-methoxy-10-(l-piperazinyl) 10,11 dihydrodibenzo [b,f]thiepin and 9.15 g. (0.048 mol) of 1-(3-chloro-propyl)-3-ethyl-2-imidazolidinone is obtained the 1-[3-[4-(8- methoxy 10,11 dihydro-dibenzo[b,f]thiepin-10-yl)-1- piperazinyl]-propyl] 3 ethyl-2-imidazolidinone-dihydrochloride, M.P. 190-192 (from ethanol/ether).

EXAMPLE 15 Analogously to Example 6, from the 8-trifiuoromethyl- 10-( l-piperazinyl)-10,1 1-dihydro-dibenzo[b,f]thiepin and the 1-(2-chloro-ethyl)-3-methyl-2-imidazolidinone is obtained the 1-[2-[4-(8-trifluoromethyl-10,1l-dihydro-dibenzo[b,f]thiepin-10-yl) 1 piperazinyl]-ethyl]-3-methyl-2- imidazolidinone.

EXAMPLE 16 250 g. of 1-[2-[4-(8-chloro-10,l1-di:hydro-dibenzoi[b ,f] thiepin-IO-yl) 1 piperazinyl]-ethyl[-3-methyl-2-imidazolidinone are mixed with 175.80 g. of lactose and 169.70 g. of potato starch. The mixture is moistened with an alcoholic solution of 10 g. of stearic acid and granulated through a sieve. After drying, g. of potato starch, 200 g. of talcum, 2.50 g. of magnesium stearate and 32 g. of colloidal silicon dioxide are mixed in and the mixture is pressed into 10,000 tablets, each weighing 100 mg. and each containing 25 mg. of active substance. Optionally, the tablets can be provided with grooves for more accurate adjustment of the dosage amount.

1 1 EXAMPLE 17 A granulate is produced from 250 g. of 1-[3-[4-(8- chloro 10,1l-dihydro-dibenzo[b,f]thiepin-10-y1)-1-piperazinyl] propyl] -3-methyl-Z-imidazolidinone-dihydrochloride, 175.90 g. of lactose and the alcoholic solution of 10 got stearic acid. After drying, the granulate is mixed with 56.60 g. of colloidal silicon dioxide, 165 g. of talcum, 20 g. of potato starch and 2.50 g. of magnesium stearate and the mixture is pressed into 10,000 drage cores. These are subsequently coated with a concentrated syrup made from 502.28 g. of crystallised saccharose, 6 g. of shellac, 10 g. of gum arabic, 0.22 g. of dyestutf and 1.5 g. of titanium dioxide and dried. The obtained drages each weigh 120 mg. and each contain 25 mg. of active substance.

EXAMPLE 18 To produce 1000 capsules each containing 25 mg. of active substance, 25 g. of 1-[2-[4-(8-methoxy-l0,11- dihydro-benzo[b,f] thiepin l yl)-1-piperazinyl]-ethyl]- 3-methyl-2-imidazolidinone are mixed with 248.0 g. of lactose. The mixture is evenly moistened with an aqueous solution of 2.0 g. of gelatine and is granulated through a suitable sieve (e.g. Sieve No. 111, Ph. Helv. V). The granulate is mixed with 10.0 g. of dried maize starch and 15.0 g. of talcum. The mixture is uniformly filled into 1000 hard gelatine capsules, size 1.

EXAMPLE 19 A suppository foundation is prepared from 2.5 g. of 1 [2 [4 (8 methylthio 10,11 dihydro-dibenzo [b,f] thiepin yl) 1 piperazinyl]-ethyl]-3-methyl-2-imidazolidinone and 167.5 g. of adeps solidus. From the mixture, 100 suppositories are filled, each containing 25 mg. of active substance.

EXAMPLE 20 .A solution of g. of-1-[2- [4-(8-chloro-10,1l-dihydrodibenzo [b,f]thiepin 10 yl) 1 piperazinyl] ethyl]-3- methyl-Z-imidazolidinone-dihydrochloride in one litre of water is filled into 1000 ampoules and sterilised. An ampoule contains a 2.5% solution of 25 mg. of active substance.

12 What is claimed is: 1. A compound of the formula wherein X is hydrogen, chloro, methyl, trifiuoromethyl, methoxy or methylthio;

R is lower alkyl of at most 4 carbon atoms; and

n is 2 or 3;

and the pharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim 1, wherein X is chloro, methoxy or methylthio; R is methyl; and n is 2 or 3.

3. A compound according to claim 1, wherein X is chloro; R-is methyl; and n is 2; and the dihydrochloride monohydrate thereof.

4. A compound according to claim 1, wherein X is methoxy; R is methyl; and n is 2; and the dihydrochloride thereof.

5. A compound according to claim 1, wherein X is methylthio; R is methyl; and n is 2; and the dihydrochloride thereof.

6. A compound according to claim 1, wherein X is chloro; R is methyl; and n is 3; and the dihydrochloride thereof.

References Cited UNITED STATES PATENTS 3,196,152 7/1965 Wright et al. 260268 X 3,337,554 8/1967 Jilex 260268 3,351,599 11/1967 Protiva et al. 260268 3,374,237 3/1968 Wright et al. 260-268 3,379,729 4/1968 Protiva et al. 260--268 3,563,993 2/1971 Schindler et al. 260268 3,524,855 8/1970 Schindler et a1 260268 DONALD G. DAUS, Primary Examiner US. Cl. X.R.

zgz gg UNITED STATES PATENTOFFICE CERTIFICATE OF CORRECTION Patent No. 3 699, 7 Dated October 17, 1972 Inventor s Walter Schindler et a1 It is certified that errorappears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

'1 Cover page, after the Inventors and before "[Geigyi" insert Assignors to CIBA-GEIGY Corporation Ardsley, New York Signed and sealed this 30th day of A ril 197R.

(SEAL) Attest:

EDWARD 1-'I.FLIL'IGHEII,JR. v C. MAI HALL DANN Attes ting Officer Commissioner of Patents 

